BACKGROUND AND OBJECTIVES: Maintaining
target-controlled propofol blood concentrations in approximately constant levels
is a technique that can be used in a simple way in the operating room. The aim
of this study was to compare in clinical and laboratorial terms propofol infusion
in children, using Shorts and Marshs pharmacokinetic parameters.METHODS: Forty-one patients of both genders, aged 4 to 12 years, physical
status ASAI or ASAII were distributed in two groups: Group S (n = 20) and Group
M (n = 21). Shorts pharmacokinetic parameters were applied to group S,
while Marshs pharmacokinetic parameters were applied to group M. Intravenous
anesthesia was induced with 30 µg.kg-1 bolus alfentanil, 3 mg.kg-1
propofol and 0.08 mg.kg-1 pancuronium. Patients were intubated and
anesthesia was maintained with N2O/O2 (60%) in controlled
mechanical ventilation. Propofol infusion in group S was 254 µg.kg-1
(30 min) followed by 216 µg.kg-1.min-1 for additional
30 minutes. Propofol infusion in group M was 208 µg.kg-1 (30
min.) followed by 170 µg.kg-1.min-1 for additional
30 minutes. Using specific pharmacokinetic parameters for each group, the goal
was a target-concentration of 4 µg.kg-1 propofol. Three blood
samples were collected (at 20, 40 and 60 minutes) to measure propofol by the
High Performance Liquid Chromatography method.RESULTS: Groups S and M were similar in age, height, weight and gender
(p > 0.05). There were no statistically significant differences between groups
in SBP, DBP, HR, FiN2O, hemoglobin SpO2 and end tidal
PETCO2. The number of repeated alfentanil boluses showed
no statistically significant difference between both groups. Bispectral index
(BIS) showed also no statistically significant differences between M0 (awaken)
and remaining moments in both groups. Error Performance Median (EPM) and Error
Performance Absolute Median (EPAM) values were statistically different between
groups in moment 60. Median propofol blood concentrations (µg.kg-1)
were significantly different between groups M and S in moment 60 and between
moments 40 and 60 in group S.CONCLUSIONS: Anesthesia with propofol using Marshs pharmacokinetic
parameters (group M) showed a lower error rate for obtaining 4 µg.kg-1
propofol target-concentration. In addition, less propofol was needed to obtain
similar clinical results. For these reasons, it should be the method of choice
for children ASA I aged 4 to 12 years.

Kruger-Thiemer 1 has equated a way
of infusing a drug as a function of time, aiming at reaching and maintaining
a constant concentration in the central compartment, provided its pharmacokinetics
could be described by a linear multicompartmental model 2,3. This
method, developed in clinical practice for continuous intravenous infusion,
had a growing interest in the 70 s, though its commercial introduction came
more recently, in the 90s 4.

Drug release is defined as automatic when a mechanical
or electronic device adjusts the doses, requiring no human intervention (manual).
Microcomputers, increasingly accepted in medicine, have allowed this automatic
drug release. So, the pharmacokinetic model of a certain anesthetic drug, processed
by a computer program, allows its administration according to the desired plasma
concentration 5. Similarly, it is possible to determine when, after
the anesthetic infusion withdrawing, the concentration compatible with consciousness
recovery will be reached.

The success of this anesthetic technique is largely
dependent on reducing operational costs. This type of infusion requires a microprocessor
controlled pump like CACI - Computerized Assisted Continuous Infusion system
4,6-8, which is not available for most anesthetic procedures.

In 1993, Bailey 9 developed an alternative
method for such infusion, which constantly varies between two or more fixed
intravenous continuous infusion rates, which decrease in a controlled manner.
Ultimately, he theoretically described a technique to calculate the rhythms
of sequential infusions needed to get close to the constant blood level desired.

This method was adapted by Vianna 10-12
for propofol continuous infusion 11, using Marsh 13 and
Short 14 pharmacokinetic parameters with the purpose of spreading
the use of target-controlled concentration, that is, the maintenance of an approximately
constant desirable blood concentration.

The aim of this study was compare, in clinical
and laboratorial terms, Marshs 13 and Shorts 14
pharmacokinetic parameters used for target-controlled propofol infusion, associated
to nitrous oxide, in children aged 4 to 12 years.

METHODS

After the Faculdade de Medicina de Botucatu Ethical
Committees, approval 41 pediatric patients of both genders, aged 4 to
12 years, physical status ASA I, scheduled for adenotonsillectomies, strabismus
corrections and bone fractures open reductions under general anesthesia were
included in the study. Patients were admitted to Hospital das Clinicas, Faculdade
de Medicina de Bauru the day before surgery.

After admission, patients were clinically evaluated
and parents or guardians were asked to authorize their inclusion on the study,
as well as the use of clinical parameters of the anesthetic protocol.

Patients were randomly allocated into two groups,
according to the pharmacokinetic program to be used:

The goal of propofol infusions in both groups
was to obtain target 4 µg.ml-1 blood concentration.

Anesthetic Techniques

After monitoring and venous accessing, anesthesia
was induced with 30 µg.kg-1 alfentanil followed by 3 mg.kg-1
bolus propofol and 0.08 mg.kg-1 pancuronium for muscle relaxation.
Next, patients were intubated and controlled mechanical ventilation was started
with 60% N2O/O2, as well as propofol continuous infusion.
Propofol bolus and maintenance infusion were administered through an infusion
pump. Should the patient exhibit clinical changes indicating superficial anesthesia,
10 µg.kg-1 bolus alfentanil were given. No additional neuromuscular
blocker doses were given. The last moment studied was at 60 minutes, even when
surgery lasted longer.

Computer programs to calculate continuous infusion
rates were: Short (PROCHIV) program and March (PROCRIV) program.

Four programs were developed to obtain approximately
constant propofol blood concentration: Short (PROCHIV) program, Marsh (PROCRIV)
program, Short (PROPOCHI) program and Marsh (PROPOCRI) program.

The first two programs Short (PROCHIV) and Marsh
(PROCRIV) calculated propofol infusion rates needed to maintain almost
constant blood concentration after a given bolus.

Starting by an execution command, the programs
prompt for patients name, record number, age, weight, gender, anesthesiologists
name, etc. Following, the initial propofol bolus was informed and the programs
return the infusion rates to be used in a single screen.

The third (Short - PROPOCHI) and fourth (Marsh
- PROPOCRI) programs calculate blood concentrations after any drug administration
scheme. In fact, these programs either emulate or calculate propofol predicted
concentration (Pc). Again, patients information is automatically asked.
After confirmation, a screen is displayed with basic data about recommended
dose ranges. Then, applied bolus and infusion rate are asked. The program accepts
any dosage, even outside typical concentration ranges. A small window shows
calculated concentration at every 25 s. New bolus or changes in infusion rate
can be made at any time. The programs are always prompting for new information.
If there is no new bolus or new infusion, one just inform value zero
when asked. This is the case when the drug is no longer being administered,
but emulation should continue to evaluate recovery conditions, which was not
the objective of our study. Finally, results are stored in data files for curves
visualization through any graphic processor. A list of results is also supplied.

Basically, programs solve the differential equations
system by the finite differences method, also known as Eulers method.
Programming language is BASIC.

Blood Propofol Measurement

At 20, 40 and 60 minutes (moment 20, moment 40
and moment 60) after beginning of anesthesia, 2 ml of venous blood samples were
collected. These samples were maintained at 4 ºC in tubes with potassium
oxalate and were used to determine blood propofol concentration (Cm).
Blood propofol was measured by High Performance Liquid Chromoatography (HPLC)
using a Shimadzu Mod. LC 10 device with fluorometric detector (Shimadzu F 535),
with wavelength between 276 mm and 310 mm, pressure of 120 psi ± 20 and
flow of 1.25 ml.min-1, according to Plummers 17
technique.

Measured propofol blood concentration (Cm)
and propofol predicted concentration (Cp) by Short program (PROPOCHI)
and Marsh program (PROPOCRI) were then statistically analyzed. Error Performance
Median (EPM) was derived, in ± %, through following the formula:

EPM ± % = Cm - Cp
/ Cp x 100

Error Performance Absolute Median (EPAM) was
also calculated, which result is similar to EPM, however without positive or
negative value:

Friedmans tests were used to compare BIS,
FiN2O, SatO2, Error Performance Median (EPM), Error Performance
Absolute Median (EPAM) and propofol blood concentration between moments within
each group. Mann-Whitney test was used to compare groups in each moment. Profile
Analysis 18 was used for SBP, DBP, HR and PETCO2,
because they present normal distribution.

Students t test was applied to check
groups homogeneity regarding to age, height and weight. Fishers Exact
test was used for gender 19.

Students t test was used to compare
alfentanil bolus repetition between groups S and M.

Results were always evaluated at a significance
level established to 5% (Figure
1 and Figure 2).

There is currently an increasing interest of
anesthesiologists in using intravenous hypnotics, analgesics and neuromuscular
blockers intravenous continuous infusions. The therapeutic effect of different
drugs is a function of their concentration in the biophase, which is determined
by blood concentration. Blood concentration may be maintained by computer assisted
infusion pumps. There is a commercially available equipment in Brazil for propofol
infusion, called Diprifusor®. This microprocessed infusion pump
uses pharmacokinetic parameters of adult patients, therefore it and is exclusive
for them since childrens pharmacokinetics is very different from adults,
especially when propofol is used 20. Propofol concentration curves
in children are better described by a tricomparmental model, with a short initial
half-life (1.5 to 4.2 minutes), due to redistribution process, followed by a
second phase (9.3 to 56 minutes) associated to high metabolic clearance in the
liver and in other large distribution volume sites. The third and final phase
(209 to 475 minutes) reflects the slow elimination process of less vascularized
tissues 21,22. So, in children, central compartment distribution
volume (343 ml.kg-1) is higher as compared to adults (228 ml.kg-1).
This determines the need to increase propofol doses during anesthetic induction.
In adult patients, to reach a blood target-concentration of 4 to 5 µg.ml-1,
1.5 to 2 mg.kg-1 venous propofol are needed, while in children require
higher doses 14, like 3 to 3.5 mg.kg-1. Propofol clearance
is also increased in pediatric patients. Marsh 13 has shown in children
propofol clearances of 32 to 57 ml.kg-1.min-1. In adult
patients, this parameter was, in average, 27 ml.kg-1.min-1.
So, higher propofol doses are required to achieve and maintain blood levels
compatible with the hypnosis needed in anesthesia.

The aim of calculating predicted drugs blood
concentrations by pharmacokinetic models is to obtain a rational regimen for
those drugs administration.

The two major pharmacokinetic model techniques
are: compartment model and exponential equations. According to Glass 4,
the latter is a rough simplification for most drugs, while the former is more
widely used for offering an intuitive understanding of the pharmacokinetic phenomenum,
among other reasons.

For most drugs, this phenomenum can be mathematically
reproducted by the three compartments model. The first, or central compartment,
is defined as the compartment where the drugs can be sampled, that is, the blood.
Drugs leave the central compartment by elimination, especially by kidneys and
by distribution to other tissues as well 23.

However, Bailey 9 has shown that it
is possible to obtain approximately constant drug blood concentrations using
conventional infusion techniques.

This allows anesthesiologists working in
places where computer assisted infusion systems are not available, like the
majority in Brazil, to perform procedures very close to those automatically
performed.

According to a suggestion of Kruger-Thiemer 1
and Glass 4, this anesthetic infusion regimen is called BET: a bolus
(B) fills the whole central compartment reaching the desired drug concentration,
followed by a constant infusion to replace the drug being eliminated (E) from
this compartment by excretion or metabolism. Superimposed to it, another infusion,
which exponentially decreases with time, is used to replace the drug being transferred
(T) to peripheral compartments.

Through the three compartments model equations,
it is very easy to assume that, in the steady state, a variable continuous infusion
rate leads to a constant blood concentration given by:

To prevent a concentration x time curve drop,
Bailey 9 proposes an initial bolus followed by continuous infusion
for 30 minutes. The infusion should be then adjusted at 1 hour intervals (30-90
min, 90-150 min, 150-210 min etc).

In fact, the numeric calculation program is executed
based on the three compartments model which calculates infusion rates needed
for the concentrations to reach a predetermined value in 30 min, 90 minutes
and subsequent hours (Table
II and Table III).
In general, infusion rate is decreased in every stage but, depending on the
initial bolus dose, it is possible that infusion may have to be increased from
the first to the second stage.

Actually, the time in which the infusion rates
are fixed could be any, and if stage intervals were decreased, concentration
would deviate less from the target. Computer emulations generate results as
precise as those obtained by Marsh 13 and Short
14.

The results obtained should be seen with some
criticism, given the limitations of the three compartments model itself. Drug
predicted blood concentration obtained by calculation is not exactly in agreement
with patients actual blood concentration. This is due firstly to pharmacokinetic
parameters obtained from measurements in a very small population. Statistically,
one cannot assure that those samples are fully representative of the universe
of individuals. Even if parameters are normalized by weight, gender and age,
clinical status and physiological differences may vary 24. Moreover,
even if drug blood concentration is exactly the same as the calculated one,
concentration needed for a given response to a stimulation differs from patient
to patient. On the other hand, the technique is justified because potential
blood concentration deviations wouldnt go beyond drugs therapeutic
window limits. That what was observed in this study: hemodynamic parameters
and hypnotic levels were similar in both groups. This study also showed that
individual variations occurred, part of the reason why collected data were different
from those computer accurately calculated.

Another interesting result was similar BIS-evaluated
hypnosis levels observed in both groups, showing that different propofol infusions
determined by pharmacokinetic programs produce concentrations within the same
therapeutic window. It must be remembered, however, that median BIS values were
lower in Group S, with the exception of M5, which was influenced by the initial
propofol bolus. These results are original, and there is no pediatric paper
in the literature studying BIS related to propofol blood concentration (Table
VI and Figure 1).
There is one study evaluating hypnosis levels in children under sevoflurane
25,26 or sevoflurane associated to N2O 27.

There is no method able to compare analgesic
depth between groups. The only data showing that groups were similar in this
aspect was the inexistence of significant difference in alfentanil bolus administration.
This complementation was minimal and restricted to 4 Group S and 5 Group M patients.
This demonstrates the analgesic efficacy of 60% N2O associated to
propofol.

This study has used, in an original manner, pharmacokinetic
parameters obtained from two researches with children aged 4 to 12 years 13,14.
For such, a software (PROCRIV, PROCHIV) was employed, based on a Baileys
study 9 proposing a simplified method to maintain a drug blood concentration
approximately constant. The technique was developed to enable anesthesiologists
to maintain a desired target blood concentration approximately constant. After
an arbitrary bolus dose, decreasing infusion rates are calculated to maintain
a stable blood level. These infusion rates are obtained from equations which
calculate sequential infusion rate schedules. The accuracy of this technique
was measured by Error Performance Median (EPM). It is an international consensus
to consider acceptable for clinical use programs using pharmacokinetic parameters
where EPM is equal to or lower than 30. EPM results in our study showed that
median levels of 8.4 in moment 20 for the Marsh group. After this, EPM increased
to 16 in moment 40 and decreased to 4.6 in moment 60, showing that, after 1
hour, predicted concentration had come close to measured concentration. Short
program 14 had an opposite behavior: EPM was 16 at 20 minutes, followed
by 12.1 and 52 at 40 and 60 minutes of propofol infusion (Table
VII and Figure 4).
Our results have shown that Marshs 13 pharmacokinetic parameters
had a good performance and remained within limits of ± 30. When predicted
and measured concentrations were compared through Error Performance Absolute
Median (EPAM), absolute values of 28.7 in moment 20, 33.2 in moment 40 and 23.6
in moment 60 were obtained for Group M; for Group S those values were 44.7 in
moment 20, 36.3 in moment 40 and 53.8 in moment 60. These results have shown
that during 1 hour of propofol infusion there was an uniformity of results with
Marshs pharmacokinetic parameters 13, while in Group S there
was a cumulative effect, reflecting in a statistically significant difference
between groups in moment 60.

Our major objective was to evaluate whether a
pharmacokinetic parameter for propofol infusion associated to N2O
in children could significantly influence hypnosis and anesthesia (Table
VI and Figure 1).
There were no significant differences in hemodynamic parameters (systolic and
diastolic blood pressure and hear rate) for both groups. SpO2, nitrous
oxide inspired concentration (FiN2O) and PETCO2
showed also no significant difference among moments and between groups. Also,
the amount of additional analgesics was similar between groups, showing that
pharmacokinetic programs are clinically equivalent. This result is understandable
because, even with pharmacokinetic differences, target blood concentrations
associated to N2O remained within the therapeutic window. In our
study, pharmacokinetic parameters were obtained from pediatric patients from
two continents (Europe and Asia) and applied to Brazilian children. It is more
likely that Shorts pharmacokinetic program, based on Hong-Kong children,
has overestimated Brazilian pediatric patients´ target blood concentration.
Conversely, Marshs pharmacokinetic parameters obtained from European children,
came closer to 4 µg.ml-1 propofol target concentration in our
patients.

Clinically, patients had similar behaviors, when
accessed three a more precise technique to evaluate hypnosis, like the microprocessed
EEG equipment - BIS (Table
VI and Figure 1).
From the laboratorial point of view, by measuring propofol blood concentration,
this similarity was not seen (Table
VII, Table VIII
and Table IX, Figure
2, Figure 3 and
Figure 4).

Concluding, the comparison between Marshs
13 and Shorts 14 parameters has shown that both
computer programs can be used in pediatrics patients, but our preference is
for PROCHIV-Marsh program for using less propofol associated to N2O,
for reaching a more accurate target concentration and inducing adequate hypnosis
levels in children aged 4 to 12 years.